Identifying ethnically relevant targets for improved treatment of ER+ breast cancer in British-Black women

Primary supervisor: Kairbaan Hodivala-Dilke, Queen Mary University of London

Secondary supervisor: Vicky Sanz Moreno, Queen Mary University of London, J Louise Jones, Queen Mary University of London, Anita Grigoriadis, King’s College London

Project

Background

Ethnic diversity and breast cancer
Relevant to the CRUK City of London Major Centre, East London has one of the most ethnically diverse populations in the country and this impacts on cancer outcomes. There is a need to better understand the biology of cancer in our ethnic minority population. British-Black women are disproportionately affected by more aggressive breast cancer subtypes, and they are more likely to be diagnosed at younger ages (prior to eligibility for screening) with more advanced stages of the disease (Jones et al., BMJ Open 2015). Socioeconomic and cultural factors influence this, but it is clear there are also biological differences. However, the biological basis for this disparity is understudied and requires urgent attention if treatment and outcomes are to improve for these women, especially now since pembrolizumab for neoadjuvant and adjuvant treatment of triple-negative early or locally advanced breast cancer has been approved by NICE in December 2022. ER+ breast cancer represents 80% of all breast cancer cases in the UK but almost no studies on ethnic diversity influences have been published relevant to ER+ breast cancer.

Focus on the tumour microenvironment

Recent RNAseq evidence has indicated that triple negative breast cancer (TNBC) of African American women have a significantly altered immune cell landscape compared with Caucasian women with TNBC (Martini et al., Cancer Discovery 2022, Please note that we have established a collaboration to expand on these findings). The reason for this is unknown, but suggests that immunotherapies may be less likely to be effective in this population.

Reduced stromal αv-integrin subunit RNA expression and enhanced malignant cell AKT1 RNA levels have also been reported in African American TNBC compared with Caucasian women (Martini et al., Cancer Discovery 2022). The α subunit is non-functional as a single subunit but heterodimerises to form the active transmembrane receptors αvβ3 and αvβ1. Reduced αvβ3 expression has been predicted to be functionally relevant in inhibiting leukocyte activation and migration and is thus likely to be involved in aberrant immune cell responses, whilst enhanced AKT1 signalling is important in increased malignant cell survival (Andrikopoulou et al., Breast 2020). Additional ethnically relevant effects on molecular alterations of the TME and the malignant cell compartment and how they cross regulate are unknown and could identify new targets relevant for breast cancer control in Black women.

Aligning with these studies, we have identified functional links between loss of stromal α integrins in ER+ breast cancer and enhanced malignant cell AKT1 signalling. Briefly:

• Loss of stromal αvβ3 and αvβ5 enhances tumour growth (Reynolds et al., Nature Medicine 2002)
• Loss of αvβ3-integrin expression in the supporting cells of tumour blood vessels (mural cells and pericytes) is sufficient to increase tumour burden and relapse rates significantly in British ER+ breast cancer patients (Wong and Munoz-Felix, Cell 2020),
• Mechanistically, loss of mural cell and pericyte αvβ3-integrin alters paracrine signals that directly affect tumour cell Rho-associated kinase (ROCK) and AKT1 signaling, increasing tumour cell invasion and survival (Crosas-Molist Phys Reviews 2022; Wong and Munoz-Felix, Cell 2020). This is of particular relevance since highly effective targeted therapies exist for this pathway.
• Effects of stromal αv-integrin loss on immune cell infiltration and activation are unknown.

Together these data suggest that loss of stromal αvβ3 expression provides a model for testing the effects on immune cell activation and infiltration in breast cancer aggressiveness relevant to British-Black women.

MBPhD Project

This MBPhd will entail understanding the biological effects of reduced stromal αv-integrin expression in the control of cancer growth and metastasis and identify ethnically relevant links with breast cancer in British-Black women. The techniques to be used will span state-of-the-art spatial transcriptomics, in vitro cell invasion and metastasis assays together with in vivo validation of target pathways.

Overall, this MBPhd will inform new strategies for improved and ethnically relevant testing and treatment of breast cancer.

References

1. Jones CE, Maben J, Lucas G, Davies EA, Jack RH, Ream E. Barriers to early diagnosis of symptomatic breast cancer: a qualitative study of Black African, Black Caribbean and White British women living in the UK. BMJ Open. 2015 Mar 13;5(3):e006944. PMID: 25770231
2. Martini R, et al. African Ancestry-Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent. Cancer Discov. 2022. PMID: 36121736
3. Wong PP, Muñoz-Félix JM, Hijazi M, Kim H, Robinson SD, De Luxán-Delgado B, Rodríguez-Hernández I, Maiques O, Meng YM, Meng Q, Bodrug N, Dukinfield MS, Reynolds LE, Elia G, Clear A, Harwood C, Wang Y, Campbell JJ, Singh R, Zhang P, Schall TJ, Matchett KP, Henderson NC, Szlosarek PW, Dreger SA, Smith S, Jones JL, Gribben JG, Cutillas PR, Meier P, Sanz-Moreno V, Hodivala-Dilke KM. Cancer Burden Is Controlled by Mural Cell-?3-Integrin Regulated Crosstalk with Tumor Cells. Cell. 2020 Jun 11;181(6):1346-1363.e21. PMID: 32473126.
4. Crosas-Molist E, Samain R, Kohlhammer L, Orgaz JL, George SL, Maiques O, Barcelo J, Sanz-Moreno V.Rho GTPase signaling in cancer progression and dissemination. Physiol Rev. 2022 Jan 1;102(1):455-510.PMID: 34541899
5. Andrikopoulou A, Chatzinikolaou S, Panourgias E, Kaparelou M, Liontos M, Dimopoulos MA, Zagouri F. The emerging role of capivasertib in breast cancer. Breast. 2022 Jun;63:157-167. PMID: 35398754