His laboratory also studies drug resistance and the role of cell-cell communication in affecting dormancy and responsiveness to endocrine therapies breast cancers that express the estrogen receptor.

[6][7][8] Clarke’s research team and collaborators discovered a new signaling network and control mechanism that contributes to the hormonal regulation of breast cancer cell proliferation and cell death in response to estrogens,[9][10] aromatase inhibitors, and antiestrogens[11] This signaling includes communication between the endoplasmic reticulum and mitochondria, and reflects novel interactions within the unfolded protein response.

His group has also identified interferon regulatory factor-1 as a breast cancer suppressor gene,[12][13] and worked on the development and application of genomic and novel bioinformatic methods in translational breast cancer studies [14][15] Clarke identified some of the first non-nuclear activities of endocrine therapies including the effects of Tamoxifen and high dose estrogens on membrane fluidity.

[19][20] He was among the pioneers to implicate the unfolded protein response (UPR) in acquired endocrine resistance[10][21] and in regulating involution in the normal mammary gland.

[25] In his studies on the endocrine-mediated regulation of breast cancer progression and cell fate, he explored the concept that the final cell-fate decision is based on integrated signaling that flows through the endoplasmic reticulum, mitochondria and nucleus.